Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 656 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 735
Cdd:cd01227     1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1314817954 736 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 787
Cdd:cd01227    75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 186 QDFQEAVTQVEFLLSQQREL---GDITGNLAQVKQRLKKLEILDDKSQELLTKARIVILRGHKLASNHHYA-------LD 255
Cdd:cd00176     3 QQFLRDADELEAWLSEKEELlssTDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDaeeiqerLE 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 256 LICQRCNELRYLSDilvneirTKRVQLSRTFKVHRLLQQARQC---CDQGECLLASQGMDKfqTKEDAQKALQDVDNFlQ 332
Cdd:cd00176    83 ELNQRWEELRELAE-------ERRQRLEEALDLQQFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKEL-E 152

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*
gi 1314817954 333 MAMPFINYDIESLQYEFDVLLSPELKAQMQNIQLKLENIRSAFQN 377
Cdd:cd00176   153 EELEAHEPRLKSLNELAEELLEEGHPDADEEIEEKLEELNERWEE 197

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 656 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 735
Cdd:cd01227     1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1314817954 736 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 787
Cdd:cd01227    75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  475 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 550
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  551 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLKELLKYS 625
Cdd:smart00325  75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                          170       180
                   ....*....|....*....|....*.
gi 1314817954  626 KEG-EGTTKLKEALDSMLELLKSVND 650
Cdd:smart00325 155 PEDhEDREDLKKALKAIKELANQVNE 180

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  687 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 762
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                           90       100
                   ....*....|....*....|..
gi 1314817954  763 YIvQAPNVDVKMLWLKEIRKIL 784
Cdd:smart00233  81 LL-QAESEEEREKWVEALRKAI 101

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  319 DAQKALQDV--DNFLQMAMPFInYDIESLQYEFDVLLSPELKAQMQNIQLKLENIRSAFQNQQAGCKSLKEvPEGAFqnl 396
Cdd:COG5422    334 DAQKLFHDVtyDHRLRDSRIEI-YQLRGYSDMRIAHNFPTSSTSFENMGKATLTNSSSSTNEPATPKAEYN-PNGVF--- 408

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  397 VPASENVMrsrmIFFSPKHVGIGYSFF----QACRIFLKVKKSWRQihaqsNVKVEAVEDSQEKNSDQS--PKLD----N 466
Cdd:COG5422    409 TLLTECYS----STCSRDELCYSISCPrrleQQARLHLKLMGGLKR-----NSSLALDKFDEEKNLWTLsvPKEVweslP 479

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  467 SLDILKNHVLNELIQTERAYVRELftvllGYRSE--MDNPQMFDLMPPLLRNK--KDVlFGNMAEIYEFhNNIFMSRLED 542
Cdd:COG5422    480 KQEIKRQEAIYEVIYTERDFVKDL-----EYLRDtwIKPLEESNIIPENARRNfiKHV-FANINEIYAV-NSKLLKALTN 552

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  543 ---CSDAPERVGPCFLERKDDFQMYAKYCQNKPRSE-LIWRKYSECAFF-------QECQRKLKHrlGLDSYLLKPVQRI 611
Cdd:COG5422    553 rqcLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKyEFEREKSVNPNFarfdhevERLDESRKL--ELDGYLTKPTTRL 630

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  612 TKYQLLLKELLKYSKEGEGTTK-LKEALDSMLELLKSVNDSMHQTAINGYVGNINEL----GKMVLQGSFNVW--LGHrK 684
Cdd:COG5422    631 ARYPLLLEEVLKFTDPDNPDTEdIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQllfkPEYVNLGLNDEYrkIIF-K 709

                          410       420       430
                   ....*....|....*....|....*....|..
gi 1314817954  685 GATKMKDFARFKPMQR---HLFLYEKAVMFCK 713
Cdd:COG5422    710 GVLKRKAKSKTDGSLRgdiQFFLLDNMLLFCK 741

Spectrin repeats;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  186 QDFQEAVTQVEFLLSQQREL---GDITGNLAQVKQRLKKLEILDDKSQELLTKARIVILRGHKLASNHHYALDLICQRCN 262
Cdd:smart00150   1 QQFLRDADELEAWLEEKEQLlasEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLE 80

                           90       100
                   ....*....|....*....|
gi 1314817954  263 ELRYLSDILVNEIRTKRVQL 282
Cdd:smart00150  81 ELNERWEELKELAEERRQKL 100

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 656 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 735
Cdd:cd01227     1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1314817954 736 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 787
Cdd:cd01227    75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  475 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 550
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  551 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLKELLKYS 625
Cdd:smart00325  75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                          170       180
                   ....*....|....*....|....*.
gi 1314817954  626 KEG-EGTTKLKEALDSMLELLKSVND 650
Cdd:smart00325 155 PEDhEDREDLKKALKAIKELANQVNE 180

Puratrophin-1 pleckstrin homology (PH) domain; Puratrophin-1 (also called Purkinje cell atrophy-associated protein 1 or PLEKHG4/Pleckstrin homology domain-containing family G member 4) contains a spectrin repeat, a RhoGEF (DH) domain, and a PH domain. It is thought to function in intracellular signaling and cytoskeleton dynamics at the Golgi. Puratrophin-1 is expressed in kidney, Leydig cells in the testis, epithelial cells in the prostate gland and Langerhans islet in the pancreas. A single nucleotide substitution in the puratrophin-1 gene were once thought to result in autosomal dominant cerebellar ataxia (ADCA), but now it has been demonstrated that this ataxia is a result of defects in the BEAN gene. Puratrophin contains a domain architecture similar to that of Dbl family members Dbs and Trio. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a RhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 649 NDSMHQTAINGYVGNINELGKMVLQGSFNVWLGHRKGatkmkdfarfkpmQRHLFLYEKAVMFCK-RRFESGEGAdryps 727
Cdd:cd13242     8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKpKKTPGGKDV----- 69

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1314817954 728 YSFKHCLKMEDVGITEHVKGDNRKFEI--RYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 787
Cdd:cd13242    70 YIYKHSIKTSDIGLTENVGDSGLKFEIwfRRRKARDTYILQATSPEIKQAWTSDIAKLLWKQ 131

Obscurin pleckstrin homology (PH) domain; Obscurin (also called Obscurin-RhoGEF; Obscurin-myosin light chain kinase/Obscurin-MLCK) is a giant muscle protein that is concentrated at the peripheries of Z-disks and M-lines. It binds small ankyrin I, a component of the sarcoplasmic reticulum (SR) membrane. It is associated with the contractile apparatus through binding with titin and sarcomeric myosin. It plays important roles in the organization and assembly of the myofibril and the SR. Obscurin has been observed as alternatively-spliced isoforms. The major isoform in sleletal muscle, approximately 800 kDa in size, is composed of many adhesion modules and signaling domains. It harbors 49 Ig and 2 FNIII repeats at the N-terminues, a complex middle region with additional Ig domains, an IQ motif, and a conserved SH3 domain near RhoGEF and PH domains, and a non-modular C-terminus with phosphorylation motifs. The obscurin gene also encodes two kinase domains, which are not part of the 800 kDa form of the protein, but is part of smaller spliced products that present in heart muscle. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 657 INGYVGNINELGKMVLQGSFNVWlghrKGATKMKDFARfkPMQRHLFLYEKAVMFCKRRFESGEGADrypSYSFKHCLKM 736
Cdd:cd13239     2 IENYPAPLQALGEPIRQGHFTVW----EEAPEVKTSSR--GHHRHVFLFKNCVVICKPKRDSRTDTV---TYVFKNKMKL 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1314817954 737 EDVGITEHVKGDNRKFEIRYSEKEEI--YIVQAPNVDVKMLWLKEIRKIlvQQK 788
Cdd:cd13239    73 SDIDVKDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL--QQR 124

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  687 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 762
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                           90       100
                   ....*....|....*....|..
gi 1314817954  763 YIvQAPNVDVKMLWLKEIRKIL 784
Cdd:smart00233  81 LL-QAESEEEREKWVEALRKAI 101

unc89 pleckstrin homology (PH) domain; unc89 is a myofibrillar protein. unc89-B the largest isoform is composed of 53 immunoglobulin (Ig) domains, 2 Fn3 domains, a triplet of SH3, DH and PH domains at its N-terminus, and 2 protein kinase domains (PK1 and PK2) at its C-terminus. unc-89 mutants display disorganization of muscle A-bands, and usually lack M-lines. The COOH-terminal region of obscurin, the human homolog of unc89, interacts via two specific Ig-like domains with the NH(2)-terminal Z-disk region of titin, a protein that connects the Z line to the M line in the sarcomere and contributes to the contraction of striated muscle. obscurin is also thought to be involved in Ca2+/calmodulin via its IQ domains, as well as G protein-coupled signal transduction in the sarcomere via its RhoGEF/DH domain. The DH-PH region of OBSCN and unc89, the C. elegans homolog, has exchange activity for RhoA and Rho-1 respectively, but not for the small GTPases homologous to Cdc42 or Rac. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 662 GNINELGKMVLQGSFNVWlghrkgatkmkdFARFKPMQRHLFLYEKAVMFCKRRFESGEgadryPSYS-FKHCLKMEDVG 740
Cdd:cd13325     1 GNIHKLGRLLRHDWFTVT------------DGEGKAKERYLFLFKSRILITKVRRISED-----RSVFiLKDIIRLPEVN 63

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1314817954 741 ITEHvKGDNRKFEIRYS-EKEEIY--IVQAPNVDVKMLWLKEIRK 782
Cdd:cd13325    64 VKQH-PDDERTFELQPKlPAFGILpiDFKAHKDEIKDYWLNEIEE 107

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  319 DAQKALQDV--DNFLQMAMPFInYDIESLQYEFDVLLSPELKAQMQNIQLKLENIRSAFQNQQAGCKSLKEvPEGAFqnl 396
Cdd:COG5422    334 DAQKLFHDVtyDHRLRDSRIEI-YQLRGYSDMRIAHNFPTSSTSFENMGKATLTNSSSSTNEPATPKAEYN-PNGVF--- 408

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  397 VPASENVMrsrmIFFSPKHVGIGYSFF----QACRIFLKVKKSWRQihaqsNVKVEAVEDSQEKNSDQS--PKLD----N 466
Cdd:COG5422    409 TLLTECYS----STCSRDELCYSISCPrrleQQARLHLKLMGGLKR-----NSSLALDKFDEEKNLWTLsvPKEVweslP 479

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  467 SLDILKNHVLNELIQTERAYVRELftvllGYRSE--MDNPQMFDLMPPLLRNK--KDVlFGNMAEIYEFhNNIFMSRLED 542
Cdd:COG5422    480 KQEIKRQEAIYEVIYTERDFVKDL-----EYLRDtwIKPLEESNIIPENARRNfiKHV-FANINEIYAV-NSKLLKALTN 552

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  543 ---CSDAPERVGPCFLERKDDFQMYAKYCQNKPRSE-LIWRKYSECAFF-------QECQRKLKHrlGLDSYLLKPVQRI 611
Cdd:COG5422    553 rqcLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKyEFEREKSVNPNFarfdhevERLDESRKL--ELDGYLTKPTTRL 630

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954  612 TKYQLLLKELLKYSKEGEGTTK-LKEALDSMLELLKSVNDSMHQTAINGYVGNINEL----GKMVLQGSFNVW--LGHrK 684
Cdd:COG5422    631 ARYPLLLEEVLKFTDPDNPDTEdIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQllfkPEYVNLGLNDEYrkIIF-K 709

                          410       420       430
                   ....*....|....*....|....*....|..
gi 1314817954  685 GATKMKDFARFKPMQR---HLFLYEKAVMFCK 713
Cdd:COG5422    710 GVLKRKAKSKTDGSLRgdiQFFLLDNMLLFCK 741

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 687 TKMKDFARFKPMQRHLFLYEKAVMFCKRRFESgegadrypSYSFKHCLKMED-VGITEHVKGD-NRKFEIrYSEKEEIYI 764
Cdd:cd00821     6 LKRGGGGLKSWKKRWFVLFEGVLLYYKSKKDS--------SYKPKGSIPLSGiLEVEEVSPKErPHCFEL-VTPDGRTYY 76

                          90
                  ....*....|....*.
gi 1314817954 765 VQAPNVDVKMLWLKEI 780
Cdd:cd00821    77 LQADSEEERQEWLKAL 92

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1314817954 685 GATKMKDFARFKPMQRHLFLYEKAVMFCKRRFESgegadrypSYSFKHCLKMEDVGITEHVKGDNRKFEIRYS------- 757
Cdd:cd01223    23 GELKIKSHEDQKKKDRYAFLFDKVLLICKSLRGD--------QYEYKEIINLSEYRIEDDPSRRTLKRDKRWSyqfllvh 94

                          90       100
                  ....*....|....*....|....*.
gi 1314817954 758 -EKEEIYIVQAPNVDVKMLWLKEIRK 782
Cdd:cd01223    95 kQGKTAYTLYAKTEELKKKWMEAIEM 120